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Dexrazoxane-afforded protection against chronic anthracycline cardiotoxicity in vivo: effective rescue of cardiomyocytes from apoptotic cell death.

Popelová O, Sterba M, Hasková P, Simůnek T, Hroch M, Guncová I, Nachtigal P, Adamcová M, Gersl V, Mazurová Y - Br. J. Cancer (2009)

Bottom Line: Dexrazoxane (60 mg kg(-1)) co-treatment was capable of overcoming DAU-induced mortality, left ventricular dysfunction, profound structural damage of the myocardium and release of cardiac troponin T and I to circulation.Moreover, for the first time, it has been shown that DEX affords significant and nearly complete cardioprotection against anthracycline-induced apoptosis in vivo and effectively suppresses the complex apoptotic signalling triggered by DAU.However, this effective cardioprotection occurred without a significant decrease in anthracycline-induced lipoperoxidation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Faculty of Medicine, Charles University in Prague, Simkova 870, Hradec Králové 500 38, Czech Republic.

ABSTRACT

Background: Dexrazoxane (DEX, ICRF-187) is the only clinically approved cardioprotectant against anthracycline cardiotoxicity. It has been traditionally postulated to undergo hydrolysis to iron-chelating agent ADR-925 and to prevent anthracycline-induced oxidative stress, progressive cardiomyocyte degeneration and subsequent non-programmed cell death. However, the additional capability of DEX to protect cardiomyocytes from apoptosis has remained unsubstantiated under clinically relevant in vivo conditions.

Methods: Chronic anthracycline cardiotoxicity was induced in rabbits by repeated daunorubicin (DAU) administrations (3 mg kg(-1) weekly for 10 weeks). Cardiomyocyte apoptosis was evaluated using TUNEL (terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling) assay and activities of caspases 3/7, 8, 9 and 12. Lipoperoxidation was assayed using HPLC determination of myocardial malondialdehyde and 4-hydroxynonenal immunodetection.

Results: Dexrazoxane (60 mg kg(-1)) co-treatment was capable of overcoming DAU-induced mortality, left ventricular dysfunction, profound structural damage of the myocardium and release of cardiac troponin T and I to circulation. Moreover, for the first time, it has been shown that DEX affords significant and nearly complete cardioprotection against anthracycline-induced apoptosis in vivo and effectively suppresses the complex apoptotic signalling triggered by DAU. In individual animals, the severity of apoptotic parameters significantly correlated with cardiac function. However, this effective cardioprotection occurred without a significant decrease in anthracycline-induced lipoperoxidation.

Conclusion: This study identifies inhibition of apoptosis as an important target for effective cardioprotection against chronic anthracycline cardiotoxicity and suggests that lipoperoxidation-independent mechanisms are involved in the cardioprotective action of DEX.

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Related in: MedlinePlus

(A–D) Scatterplots of the cardiac function (LV fractional shortening (FS)) vs activity of individual caspases as determined by Spearman's correlation analyses: caspases 3/7 (A), caspase 8 (B), caspase 9 (C) and caspase 12 (D). LU, luminescence units; FU, fluorescence units.
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fig6: (A–D) Scatterplots of the cardiac function (LV fractional shortening (FS)) vs activity of individual caspases as determined by Spearman's correlation analyses: caspases 3/7 (A), caspase 8 (B), caspase 9 (C) and caspase 12 (D). LU, luminescence units; FU, fluorescence units.

Mentions: Determination of the activity of all major caspases associated with apoptotic signalling showed triggering of multiple apoptotic pathways in the LV myocardium of DAU-treated animals. As seen in Figure 5A, chronic ANT treatment resulted in a significant increase in the activity of the executive downstream caspases 3 and 7, in comparison with that in the control group. In addition, the activities of caspases 8, 9 and 12 were also found to be increased in the DAU group (Figure 5B–D). In the DEX co-treated animals, the activity of the executive caspases 3/7 was significantly lower than that in the DAU-alone group (Figure 5A). Furthermore, activation of all major upstream pathways (i.e., caspases 8, 9 and 12) was effectively prevented by DEX co-treatment. There were no significant differences in the activities of individual caspases between the control and the DEX+DAU group (Figure 5B–D). Interestingly, the activities of these caspases showed a significant and strong correlation with LV systolic function (Figure 6A–D).


Dexrazoxane-afforded protection against chronic anthracycline cardiotoxicity in vivo: effective rescue of cardiomyocytes from apoptotic cell death.

Popelová O, Sterba M, Hasková P, Simůnek T, Hroch M, Guncová I, Nachtigal P, Adamcová M, Gersl V, Mazurová Y - Br. J. Cancer (2009)

(A–D) Scatterplots of the cardiac function (LV fractional shortening (FS)) vs activity of individual caspases as determined by Spearman's correlation analyses: caspases 3/7 (A), caspase 8 (B), caspase 9 (C) and caspase 12 (D). LU, luminescence units; FU, fluorescence units.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2736842&req=5

fig6: (A–D) Scatterplots of the cardiac function (LV fractional shortening (FS)) vs activity of individual caspases as determined by Spearman's correlation analyses: caspases 3/7 (A), caspase 8 (B), caspase 9 (C) and caspase 12 (D). LU, luminescence units; FU, fluorescence units.
Mentions: Determination of the activity of all major caspases associated with apoptotic signalling showed triggering of multiple apoptotic pathways in the LV myocardium of DAU-treated animals. As seen in Figure 5A, chronic ANT treatment resulted in a significant increase in the activity of the executive downstream caspases 3 and 7, in comparison with that in the control group. In addition, the activities of caspases 8, 9 and 12 were also found to be increased in the DAU group (Figure 5B–D). In the DEX co-treated animals, the activity of the executive caspases 3/7 was significantly lower than that in the DAU-alone group (Figure 5A). Furthermore, activation of all major upstream pathways (i.e., caspases 8, 9 and 12) was effectively prevented by DEX co-treatment. There were no significant differences in the activities of individual caspases between the control and the DEX+DAU group (Figure 5B–D). Interestingly, the activities of these caspases showed a significant and strong correlation with LV systolic function (Figure 6A–D).

Bottom Line: Dexrazoxane (60 mg kg(-1)) co-treatment was capable of overcoming DAU-induced mortality, left ventricular dysfunction, profound structural damage of the myocardium and release of cardiac troponin T and I to circulation.Moreover, for the first time, it has been shown that DEX affords significant and nearly complete cardioprotection against anthracycline-induced apoptosis in vivo and effectively suppresses the complex apoptotic signalling triggered by DAU.However, this effective cardioprotection occurred without a significant decrease in anthracycline-induced lipoperoxidation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Faculty of Medicine, Charles University in Prague, Simkova 870, Hradec Králové 500 38, Czech Republic.

ABSTRACT

Background: Dexrazoxane (DEX, ICRF-187) is the only clinically approved cardioprotectant against anthracycline cardiotoxicity. It has been traditionally postulated to undergo hydrolysis to iron-chelating agent ADR-925 and to prevent anthracycline-induced oxidative stress, progressive cardiomyocyte degeneration and subsequent non-programmed cell death. However, the additional capability of DEX to protect cardiomyocytes from apoptosis has remained unsubstantiated under clinically relevant in vivo conditions.

Methods: Chronic anthracycline cardiotoxicity was induced in rabbits by repeated daunorubicin (DAU) administrations (3 mg kg(-1) weekly for 10 weeks). Cardiomyocyte apoptosis was evaluated using TUNEL (terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling) assay and activities of caspases 3/7, 8, 9 and 12. Lipoperoxidation was assayed using HPLC determination of myocardial malondialdehyde and 4-hydroxynonenal immunodetection.

Results: Dexrazoxane (60 mg kg(-1)) co-treatment was capable of overcoming DAU-induced mortality, left ventricular dysfunction, profound structural damage of the myocardium and release of cardiac troponin T and I to circulation. Moreover, for the first time, it has been shown that DEX affords significant and nearly complete cardioprotection against anthracycline-induced apoptosis in vivo and effectively suppresses the complex apoptotic signalling triggered by DAU. In individual animals, the severity of apoptotic parameters significantly correlated with cardiac function. However, this effective cardioprotection occurred without a significant decrease in anthracycline-induced lipoperoxidation.

Conclusion: This study identifies inhibition of apoptosis as an important target for effective cardioprotection against chronic anthracycline cardiotoxicity and suggests that lipoperoxidation-independent mechanisms are involved in the cardioprotective action of DEX.

Show MeSH
Related in: MedlinePlus